Sustained release emulsions

ABSTRACT

Ophthalmic methods and compositions are disclosed where particles of the dispersed phase of emulsions are themselves dispersed and stably maintained in physical separation by lightly crosslinked, water swellable polymers present in an aqueous polymeric system formulated for administration to the eye in drop or ribbon form. Medicament is dissolved in that dispersed phase is delivered over a sustained release period.

FIELD OF THE INVENTION

This invention relates to topical ophthalmic preparations and methods.More particularly, this invention relates to topical ophthalmicpreparations and methods involving medicaments that are not very solublein aqueous media.

BACKGROUND OF THE INVENTION

Oily drugs such as protoglandins (PGs) have been recognized as usefulfor the reduction of intraocular pressure if topically applied. Theirpreferred administration in aqueous solutions has also been recognized.See U.S. Pat. No. 4,952,851. Isotonization agents such as sodiumchloride and thickening agents such as carboxyvinyl polymer, togetherwith buffering agents, stabilizers, etc. have also been proposed fortheir formulation in ophthalmic compositions. Oil diluents fornonaqueous solutions and suspensions have also been proposed. See U.S.Pat. No. 5,405,846.

However, oily drugs present solubility problems in aqueous media, andthey are not readily dispersed in such media. Surfactants can beemployed to form emulsions in which the oily drugs are dissolved orsuspended. See U.S. Pat. No. 4,347,238. However, stability of theemulsion can then become a problem. Over time, oily particles formingthe disperse phase of the emulsion can agglomerate or coalesce andseparate from the aqueous continuous phase. The presence of salts and/orsoluble polymers used to increase viscosity can exacerbate the problemby competing for water, thereby increasing the tendency of the oilydisperse phase to separate from the aqueous continuous phase. Indeed,avoidance of large quantities (i.e., greater than 0.3%) of the salt of alightly cross-linked polyacrylic acid has been recommended because of atendency to gel the water phase, making the emulsion immobile. See U.S.Pat. No. 4,347,238 at col. 3, lines 7-10.

Furthermore, the irritating effect of ionic surfactants has been said tobe a limiting factor on commercialization of ophthalmic compositions inthe form of oil-in-water emulsions. See International Publication WO94/05298 (PCT/US93/00044).

One approach proposed for overcoming some of the foregoing difficultiesis the conversion of classical emulsions to submicron emulsionscomprising an oil, a phospholipid, a non-ionic surfactant and an aqueouscomponent. Unexplained soothing effects were attributed to the colloidalparticles, regardless of whether hydrophobic drugs contained in theparticles or hydrophilic drugs soluble in the aqueous component areemployed. See WO 94/05298 at application page 8.

Despite the promise of such advantages, potential problems associatedwith settling of particles and/or their agglomeration might still beencountered. Moreover, such problems could still be exacerbated in thepresence of salts and/or soluble polymers used to enhance viscosity.

It would, therefore, be desirable to overcome or ameliorate drawbacks ofthe sort previously noted, especially when dealing with oilymedicaments.

It would also be desirable to enhance the bioavailability of solidmedicaments of the type which are only sparingly soluble in water. Suchdrugs have been satisfactorily dispersed in aqueous polymeric systems ofthe sustained release type, such as those based on the disclosure ofcommonly assigned U.S. Pat. No. 5,192,535. However, the bioavailabilityof the drugs during the sustained release period is inhibited by theirweak solubility.

OBJECTS AND SUMMARY

It is a general object of the present invention to provide novel methodsand compositions which provide for sustained release aqueous polymericsystems containing emulsions to be advantageously employed in topicalophthalmic applications.

It is another object of the present invention to provide novel methodsand compositions wherein the ability to effectively administer oilymedicaments is enhanced.

It is an additional object of the present invention to provide novelmethods and compositions wherein the tendency of oily medicaments toseparate and/or agglomerate in aqueous media is inhibited.

It is a further object of the present invention to provide novel methodsand compositions that enhance the ability to effectively use solidmedicaments of the type that are only weakly water soluble.

It is yet a further object of the present invention to enhance thebioavailability, during a sustained release period, of such solidmedicaments.

The foregoing and other objects and advantages are intended to berealized through preferred forms of the invention wherein particles ofthe dispersed phase of an emulsion of water and oil and/or lipids, arethemselves dispersed and maintain in stable physical separation by alightly crosslinked, water swellable polymer present in the aqueouspolymeric system in an amount in excess of 0.3%, more preferably inexcess of 0.5%, by weight of the composition. Preferably, the polymer ispolyacrylic acid crosslinked with divinyl glycol.

In the most preferred forms of the invention, the disperse phase of theemulsion contains dissolved medicament selected from oily medicaments(e.g., prostaglandins) and solid medicaments sparingly soluble in water(e.g., 21-aminosteroids).

The pH and osmolality of the composition is adjusted for compatibilitywith the eye, and a suitable viscosity is established for administrationto the eye in drop or ribbon form.

DETAILED DESCRIPTION

In accordance with the present invention, water, an oil and/or lipid, alightly cross-linked, water swellable polymer, and a medicament arecombined in an aqueous system. Particles of the disperse phase of theemulsion are themselves dispersed in that aqueous polymeric system so asto enhance maintenance of the physical separation of such particles.

Rather than using large quantities of the polymer, the present inventionrelies on including an amount of the polymer sufficient to stablymaintain that physical separation of the particles of the disperse phaseof the emulsion within the aqueous polymeric system. At least about 0.5%by weight of the total product is preferred. Generally, the range ofpolymer will be between about 0.5% to about 6.5%, usually about 0.5% toabout 2.0%.

The emulsion may be based on oils and/or lipids, with use of lipidsbeing preferred. However, any suitable oils or lipids will suffice.Examples of suitable oils include vegetable oils, mineral oils, mediumchain trigliceride oils (which may be a component of vegetable oil),oily fatty acids, and mixtures of any of them. For additionalidentification of suitable oils, see the disclosures of oils in U.S.Pat. No. 4,347,238 at Col. 3, U.S. Pat. No. 5,405,846 at Col. 6, andInternational Publication WO 94/05298 at application pages 9-10, whichare all hereby incorporated by reference. Preferred lipids arephospholipid compounds or mixtures of phospholipids such as lecithin,phosphatidylcholine, phosphatidyethanolamine or mixtures thereof. Seethe disclosure of examples of such compounds or mixtures at applicationpage 10 of International Publication WO 94/05298 which is herebyincorporated by reference. Most preferred is a phospholipid emulsioncommercially available under the brand name INTRALIPID.

    ______________________________________                                        Soybean Oil        10.0       g                                               Phospholipids      1.2        g                                               (from powdered egg yolk)                                                      Glycerin, USP      2.25       g                                               Water for injection                                                                              qs                                                         ______________________________________                                    

The pH of INTRALIPID normally ranges from about 6.0 to about 8.9 but thepH may readily be adjusted in a conventional manner such as by theaddition of sodium hydroxide.

Since the lipids already contain hydrophilic functionalities,surfactants may not be necessary or even desirable when lipids aloneform the disperse phase of the emulsion. However, surfactants may stillbe employed; and when oil is a substantial component of the dispersephase of the emulsion, surfactants generally will be employed. Preferredsurfactants are non-ionic, and generally a non-ionic oxide condensate ofan organic compound which contains one or more hydroxyl groups will beselected. Polysorbate 80 is most preferred. For additionalidentification of suitable surfactants, see the disclosure ofsurfactants in U.S. Pat. No. 4,347,238 at column 3 and in theInternational Publication WO 94/05298 at application pages 10-11 whichare hereby incorporated by reference. Generally, the more oil presentthe more surfactant would be employed. However, the mechanicalseparation of particles of the disperse phase of the emulsion in theaqueous polymeric system in accordance with the present inventionpermits use of comparatively less surfactant, thereby reducingirritation potential.

The emulsions employed in carrying out the present invention includeboth macroemulsions and microemulsions. It is believed that, from theoutset of administration and throughout sustained release,macroemulsions whose disperse phase particles are themselves dispersedin the aqueous polymer system will present benefits in being soothing tothe eye. However, it is believed that microemulsions will presentadditional comfort benefits by reason of either the smaller particlesize or the previously mentioned, unexplained physiological mechanismmentioned in International Publication WO 94/052989, or both.

The amount of oil and/or lipid which establishes the disperse phase ofthe emulsion can be varied. Generally, it will range from about 0.1% toabout 60% by weight of the entire composition preferably about 1% toabout 20% of the entire composition. Surfactants, when employed, willgenerally amount to less than about 1.0% by weight of the entirecomposition, preferably in the range of from about 0.001% to about 0.2%.

The aqueous phase of the emulsion will preferably be comprised ofdistilled water and sodium chloride and will preferably be maintainedisotonic with the lacrimal fluid. Osmotic pressure may be adjusted to apressure of from about 10 to about 400 OsM, more preferably from about100 to about 300 OsM, and pH will be controlled to be in any rangeacceptable for administration to the eye, generally a range of about 5.0to about 9.0. Suitable adjuvants and excipients may also be employed.Typical such additives may include sodium edetate (EDTA), mannitol,sodium hydroxide, and preservatives like benzalkonium chloride (BAK).

The lightly crosslinked polymer systems preferred for use in the presentinvention are the aqueous suspensions of carboxyvinyl polymers describedin U.S. Pat. No. 5,192,535, whose entire disclosure concerning theirpreparation, characteristics and properties is incorporated herein byreference. However, any other suitable lightly crosslinked, watersoluble polymer may be employed, for example,polyhydroxyethylmethacrylate or polyvinyl pyrolidone. The amount ofwater swellable polymer will preferably range from greater than 0.3% toabout 6.5% by weight and preferably from about 0.5% to about 4.5% byweight, and more preferably from about 1.0% to about 2.0% of the totalcomposition. Most preferably, the polymer is polycarbophil, apolyacrylic acid polymer lightly crosslinked with divinyl glycol.

The viscosity of the aqueous suspension of the polymer will be desirablyadjusted in a conventional manner to be in a range suitable forconvenient administration to the eye in drop or ribbon form. Generally,that viscosity will be in the range of about 1,000 to about 100,000centepoises.

It is envisioned that certain benefits of the present invention can berealized independently of the medicament and its solubility. Overall,drug content will vary, usually from about .001% to about 10%, by weightof the entire composition.

In its most preferred form, however, the benefits of the presentinvention will be realized through implementation with oily drugs thatare dissolved in the oil and/or lipid. Prostaglandins and derivativesthereof are especially preferred medicaments envisioned for use, aloneor in combination therapy, in that implementation of the presentinvention. As used herein, the term oily medicament means a medicamentthat is hydrophobic and that is liquid at physiological pH, temperatureand osmolality. The freebase form of pilocarpine also constitutes anoily drug. Other examples will be recognized by those skilled in theart.

Prostaglandins (PGs) were initially isolated from sheep seminal vesiclesand human seminal fluid but may be found in most mammalian tissues. Theyare a group of eicosanoids which contain cyclical fatty acids, includingchain moities, and are known to possess diverse biological activities.These activities include stimulation of smooth muscle, dilation of smallarteries, bronchial dilation, and lowering of blood pressure, amongothers.

The primary PGs are classified based on the structural feature of a5-membered cyclical moiety into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs,PGGs, PGHs, PGIs, and PGJs. They are further classified based on thepresence or absence of unsaturation and oxidation in the chain moietyusing subscripts 1, 2 and 3 to designate the location of unsaturationand oxidation. They are further subclassified according to theconfiguration of a hydroxy group into alpha and beta configurations. Thechemical structure and classification of these compounds are known andare described, for instance, in U.S. Pat. No. 5,405, 846, the disclosureof which is incorporated herein by reference. Other patents describingprostaglandins and their use, either alone or in combination with othermedicaments, are disclosed in the above-referenced patent and in U.S.Pat. No. 4,599,353; U.S. Pat. No. 4,952, 581; and U.S. Pat. No.4,883,819; the disclosures of which are incorporated herein byreference.

As the foregoing patents indicate, prostaglandins and their derivativesand conjugates are particularly useful for the reduction of intraocularpressure when applied to the surface of the eye. Moreover,prostaglandins may be combined with other drugs, such as adrenergicblocking agents, to relieve intraocular pressure. It is contemplatedthat any of the prostaglandins and their derivatives and conjugates maybe used alone or in combination with other drugs in accordance with thepresent invention. Formulations of the present inventions incorporatingprostaglandins, either alone or in combination with other drugs, areparticularly useful for the reduction of intraocular pressure caused bychronic glaucoma.

The amount of any oily medicament employed will vary depending onsolubility in the disperse phase of the emulsion. Complete solubility ispreferred. In addition, use of an amount of oily medicament that wouldestablish a saturated solution in the given quantity of oil and/or lipidcould be desirable. However, consideration of activity and irritationpropensity will also govern the medicament content. For example,prostaglandins are irritating at high concentrations in the eye and havehigh activity at low concentrations, so an amount of 0.005% or less,down to about 0.001% is preferred.

Especially significant benefits of the present invention are alsoenvisioned where the medicament is a solid drug that is only weaklysoluble in water, but quite soluble in the oil and/or lipid. Such drugs,for example, fluoromethalone, have been satisfactorily suspended inaqueous polymeric suspensions of polycarbophil for sustained delivery.However, when dissolved in the oil and/or lipid in accordance with thepresent invention, their bioavailability to the targeted issue may beenhanced. Since dissolution from a solid is not then required, thetransfer rate into an aqueous phase may be enhanced so a higherpermeation may be achieved, thereby by presenting a higher concentrationof dissolved drug to the targeted tissue during the sustained release.Other examples of solid drugs which are weakly soluble in water, andwhose bioavailability can be similarly enhanced by dissolution in theoil and/or lipid, will be recognized and appreciated by those skilled inthe art.

The following Table I provides examples of compositions that can be usedto administer oily medicaments alone or in combination therapy inaccordance with the present invention.

                  TABLE I                                                         ______________________________________                                        OILY COMPOUNDS/COMBINATIONS                                                   Composition                                                                   Weight %                                                                      ______________________________________                                                     Ex-     Ex-     Ex-   Ex-   Ex-                                  Component    ample 1 ample 2 ample 3                                                                             ample 4                                                                             ample 5                              ______________________________________                                        PGF.sub.2α -1-Isopropyl Ester                                                        0.005   --      --    0.005 0.005                                Pilocarpine  --      2.0     --    --    --                                   Scopolamine  --      --      0.25  --    --                                   Levobunolol HCl                                                                            --      --      --    0.1   --                                   Timolol Maleate                                                                            --      --      --    --    0.25                                 EDTA         0.1     0.1     0.1   0.1   0.1                                  Sodium Chloride                                                                            0.2     --      0.2   0.2   0.2                                  Mannitol     --      2.0     --    --    --                                   Polycarbophil                                                                              1.2     1.15    1.15  1.2   1.2                                  Oil/Lipids   1       5       10    5     5                                    BAK          0.005   0.005   0.005 0.008 0.008                                Sodium Hydroxide                                                                           q.s.    q.s.    q.s.  q.s.  q.s.                                 Purified Water                                                                             q.s. 100                                                                              q.s. 100                                                                              q.s. 100                                                                            q.s. 100                                                                            q.s. 100                             pH           6.0     5.4     5.5   6.0   6.0                                  ______________________________________                                        Component  Example 6 Example 7                                                                              Example 8                                                                             Example 9                               ______________________________________                                        21-Aminosteroid                                                                          0.25      --       --      --                                      (U74006F)                                                                     Batismastat-*                                                                            --        0.3      --      --                                      Fluorometholone                                                                          --        --       0.1     --                                      Lexipfant-**                                                                             --        --       --      0.3                                     EDTA       0.1       0.1      0.1     0.1                                     Sodium Chloride                                                                          0.2       0.2      0.2     0.2                                     Polycarbophil                                                                            1.0       1.15     1.2     1.3                                     Oil/Lipids 20        10       10      20                                      BAK        0.005     0.005    0.005   0.005                                   Polysorbate 80                                                                           0.2       --       --      --                                      Sodium Hydroxide                                                                         q.s       q.s      q.s     q.s                                     Purified Water                                                                           q.s 100   q.s 100  q.s 100 q.s 100                                 pH         6.0       6.0      5.6     6.0                                     ______________________________________                                         *The chemical name is:                                                         4(N-hydroxyamino)-2R-isobutyl-3S-(thienylthiomethyl)-succinyl!-L-phenyla    anine-N-methylamide                                                            **The chemical name is:                                                       (S)4-methyl-2-{methyl- 4-(2-methyl-imidazo{4,5-c}pyridin-1-ylmethyl)-benz    nesulfonyl!-amino}-pentanoic acid ethyl ester                             

The Examples 1-9 listed in Table I can be prepared on a 100gm scale inthe following manner:

1. An oil phase containing triglyceride, oily medicament or waterinsoluble drug, and lipid is heated to about 50° C.

2. An aqueous phase, containing water, isotonic agent, EDTA, and watersoluble non-ionic surfactant, is heated to about 50° C.

3. The two phases are combined together, mixing well with a magneticstirrer to produce a coarse emulsion. The emulsion is further heated toabout 80° C.

4. The emulsion is homogenized by a homogenizer at 10,000 rpm for 3minutes and then rapidly cooled to below 40° C. in an ice bath.

5. After cooling, the emulsion is sonicated by a probe ultrasonicprocessor for 5-10 minutes until a translucent microemulsion isobtained. The pH adjustment to the target pH is made after thesonication step.

6. A polymer system is prepared separately by hydrating the polymer inwater and then adding EDTA, isotonic agent, and water soluble drug.

7. The pH of the polymer system is adjusted to target pH of theformulation with NaOH.

8. The microemulsion is added to the polymer system and these componentsare mixed.

The foregoing Examples are illustrative and are not to be consideredlimiting of the present invention. Departure from specifics set fortheither in those examples or elsewhere herein can be made withoutdeparting from the spirit and scope of the invention as defined in theappended claims.

What is claimed is:
 1. A method of preparing a sustained release topicalophthalmic composition for administration of an oily medicament or solidmedicament sparingly soluble in water to the eye comprising:dissolving aleast some of the oily medicament or solid medicament sparingly solublein water in the disperse phase of an oil, lipid or oil and lipidemulsion, dispersing the disperse phase of the oil, lipid or oil andlipid emulsion which has such medicament dissolved therein in an aqueoussuspension of a lightly crosslinked, water swellable polymer present inan amount in excess of 0.3% by weight of the composition adjusting thepH and osmolality for compatibility with the eye, and establishing aviscosity of the system for administration to the eye in drop or ribbonform.
 2. The method according to claim 1, wherein said polymer ispresent in an amount in the range of about 0.5% to about 6.5% by weightof the composition.
 3. The method according to claim 2, wherein saidpolymer is present in an amount in the range of about 0.5% to about 2%by weight of the composition.
 4. The method according to claim 1,wherein said polymer is present in an amount in the range of about 0.5%to about 6.5% by weight of the composition.
 5. The method according toclaim 4, wherein said polymer is present in an amount in the range ofabout 0.5% to about 2% by weight of the composition.